This invention relates to the fields of pharmaceutical and organic chemistry and provides novel compounds with nitrogen-containing non-basic side chains, which are useful for the treatment of the various medical indications associated with post-menopausal syndrome, and uterine fibroid disease, endometriosis, and aortal smooth muscle cell proliferation. The present invention also relates to pharmaceutical compositions of the compounds of the present invention.
xe2x80x9cPost-menopausal syndromexe2x80x9d is a term used to describe various pathological conditions which frequently affect women who have entered into or completed the physiological metamorphosis known as menopause. Although numerous pathologies are contemplated by the use of this term, three major effects of post-menopausal syndrome are the source of the greatest long-term medical concern: osteoporosis, cardiovascular effects such as hyperlipidemia, and estrogen-dependent cancer, particularly breast and uterine cancer.
Osteoporosis describes a group of diseases which arise from diverse etiologies, but which are characterized by the net loss of bone mass per unit volume. The consequence of this loss of bone mass and resulting bone fracture is the failure of the skeleton to provide adequate structural support for the body.
One of the most common types of osteoporosis is that associated with menopause. Most women lose from about 20% to about 60% of the bone mass in the trabecular compartment of the bone within 3 to 6 years after the cessation of mensus. This rapid loss is generally associated with an increase of bone resorption and formation. However, the resorptive cycle is more dominant and the result is a net loss of bone mass. Osteoporosis is a common and serious disease among post-menopausal women.
There are an estimated 25 million women in the United States, alone, who are afflicted with this disease. The results of osteoporosis are personally harmful and also account for a large economic loss due its chronicity and the need for extensive and long term support (hospitalization and nursing home care) from the disease sequelae. This is especially true in more elderly patients. Additionally, although osteoporosis is not generally thought of as a life threatening condition, a 20% to 30% mortality rate is related with hip fractures in elderly women. A large percentage of this mortality rate can be directly associated with post-menopausal osteoporosis.
The most vulnerable tissue in the bone to the effects of post-menopausal osteoporosis is the trabecular bone. This tissue is often referred to as spongy or cancellous bone and is particularly concentrated near the ends of the bone (near the joints) and in the vertebrae of the spine. The trabecular tissue is characterized by small osteoid structures which inter-connect with each other, as well as the more solid and dense cortical tissue which makes up the outer surface and central shaft of the bone. This inter-connected network of trabeculae gives lateral support to the outer cortical structure and is critical to the bio-mechanical strength of the overall structure.
In post-menopausal osteoporosis, it is, primarily, the net resorption and loss of the trabeculae which leads to the failure and fracture of bone. In light of the loss of the trabeculae in post-menopausal women, it is not surprising that the most common fractures are those associated with bones which are highly dependent on trabecular support, e.g., the vertebrae, the neck of the weight bearing bones such as the femur and the fore-arm. Indeed, hip fracture, collies fractures, and vertebral crush fractures are hall-marks of post-menopausal osteoporosis.
At this time, the only generally accepted method for treatment of post-menopausal osteoporosis is estrogen replacement therapy. Although therapy is generally successful, patient compliance with the therapy is low primarily because estrogen treatment frequently produces undesirable side effects.
Prior to menopause, most women have less incidence of cardiovascular disease than age-matched men. Following menopause, however, the rate of cardiovascular disease in women slowly increases to match the rate seen in men. This loss of protection has been linked to the loss of estrogen and, in particular, to the loss of estrogen""s ability to regulate the levels of serum lipids. The nature of estrogen""s ability to regulate serum lipids is not well understood, but evidence to date indicates that estrogen can upregulate the low density lipid (LDL) receptors in the liver to remove excess cholesterol. Additionally, estrogen appears to have some effect on the biosynthesis of cholesterol, and other beneficial effects on cardiovascular health.
It has been reported in the literature that post-menopausal women undergoing estrogen replacement therapy experience a return of serum lipid concentrations to those of the pre-menopausal state. Thus, estrogen would appear to be a reasonable treatment for this condition. However, the side-effects of estrogen replacement therapy are not acceptable to many women, thus limiting the use of this therapy. An ideal therapy for this condition would be an agent which would regulate the serum lipid level as does estrogen, but would be devoid of the side-effects and risks associated with estrogen therapy.
The third major pathology associated with post-menopausal syndrome is estrogen-dependent breast cancer and, to a lesser extent, estrogen-dependent cancers of other organs, particularly the uterus. Although such neoplasms are not solely limited to a post-menopausal women, they are more prevalent in the older, post-menopausal population. Current chemotherapy of these cancers has relied heavily on the use of anti-estrogen compounds such as, for example, Tamoxifen. Although such mixed agonist-antagonists have beneficial effects in the treatment of these cancers, and the estrogenic side-effects are tolerable in acute life-threatening situations, they are not ideal. For example, these agents may have stimulatory effects on certain cancer cell populations in the uterus due to their estrogenic (agonist) properties and they may, therefore, be contraproductive in some cases. A better therapy for the treatment of these cancers would be an agent which is an anti-estrogen compound having negligible or no estrogen agonist properties on reproductive tissues.
In response to the clear need for new pharmaceutical agents which are capable of alleviating the symptoms of, inter alia, post-menopausal syndrome, the present invention provides new compounds, pharmaceutical compositions thereof, and methods of using such compounds for the treatment of post-menopausal syndrome and other estrogen-related pathological conditions such as those mentioned below. The reduction of bone density and mass leading to osteoporosis that more rarely occurs in men is also tied to the loss of hormonal regulation and is, therefore, also a target for therapy according to the compounds and methods of the current invention.
Uterine fibrosis is an old and ever present clinical problem known by a variety of names, including uterine hypertrophy, uterine lieomyomata, myometrial hypertrophy, fibrosis uteri, and fibrotic metritis. Essentially, uterine fibrosis is a condition where there is an inappropriate deposition of fibroid tissue on the wall of the uterus.
This condition is a cause of dysmenorrhea and infertility in women. The exact cause of this condition is poorly understood but evidence suggests that it is an inappropriate response of fibroid tissue to estrogen. Such a condition has been produced in rabbits by daily administrations of estrogen for 3 months. In guinea pigs, the condition has been produced by daily administration of estrogen for four months. Further, in rats, estrogen causes similar hypertrophy.
The most common treatment of uterine fibrosis involves surgical procedures both costly and sometimes a source of complications such as the formation of abdominal adhesions and infections. In some patients, initial surgery is only a temporary treatment and the fibroids regrow. In those cases a hysterectomy is performed which effectively ends the fibroids but also the reproductive life of the patient. Also, gonadotropin releasing hormone antagonists may be administered, yet their use is tempered by the fact they can lead to osteoporosis.
Endometriosis is a condition of severe dysmenorrhea, which is accompanied by severe pain, bleeding into the endometrial masses or peritoneal cavity and often leads to infertility. The cause of the symptoms of this condition appear to be ectopic endometrial growths which respond inappropriately to normal hormonal control and are located in inappropriate tissues. Because of the inappropriate locations for endometrial growth, the tissue seems to initiate local inflammatory-like responses causing macrophage infiltration and a cascade of events leading to initiation of the painful response. The exact etiology of this disease is not well understood and its treatment by hormonal therapy is diverse, poorly defined, and marked by numerous unwanted and perhaps dangerous side effects.
One of the treatments for this disease is the use of low dose estrogen to suppress endometrial growth through a negative feedback effect on central gonadotropin release and subsequent ovarian production of estrogen; however, it is sometimes necessary to use continuous estrogen to control the symptoms. This use of estrogen can often lead to undersirable side effects and even the risk of endometrial cancer.
Another treatment consists of continuous administration of progestins which induces amenorrhea and by suppressing ovarian estrogen production can cause regressions of the endometrial growths. The use of chronic progestin therapy is often accompanied by the unpleasant CNS side effects of progestins and often leads to infertility due to suppression of ovarian function.
A third treatment consists of the administration of weak androgens, which are effective in controlling the endometriosis; however, they induce severe masculinizing effects. Several of these treatments for endometriosis have also been implicated in causing a mild degree of bone loss with continued therapy. Therefore, new methods of treating endometriosis are desirable.
Aortal smooth muscle cell proliferation plays an important role in diseases such as atherosclerosis and restenosis. Vascular restenosis after percutaneous transluminal coronary angioplasty (PTCA) has been shown to be a tissue response characterized by an early and late phase. The early phase occuring hours to days after PTCA is due to thrombosis with some vasospasms while the late phase appears to be dominated by excessive proliferation and migration of aortal smooth muscle cells. In this disease, the increased cell motility and colonization by such muscle cells and macrophages contribute significantly to the pathogenesis of the disease. The excessive proliferation and migration of vascular aortal smooth muscle cells may be the primary mechanism to the reocclusion of coronary arteries following PTCA, atherectomy, laser angioplasty and arterial bypass graft surgery. See xe2x80x9cIntimal Proliferation of Smooth Muscle Cells as an Explanation for Recurrent Coronary Artery Stenosis after Percutaneous Transluminal Coronary Angioplasty,xe2x80x9d Austin et al., Journal of the American College of Cardiology 8: 369-375 (Aug. 1985).
Vascular restenosis remains a major long term complication following surgical intervention of blocked arteries by percutaneous transluminal coronary angioplasty (PTCA), atherectomy, laser angioplasty and arterial bypass graft surgery. In about 35% of the patients who undergo PTCA, reocclusion occurs within three to six months after the procedure. The current strategies for treating vascular restenosis include mechanical intervention by devices such as stents or pharmacologic therapies including heparin, low molecular weight heparin, coumarin, aspirin, fish oil, calcium antagonist, steroids, and prostacyclin. These strategies have failed to curb the reocclusion rate and have been ineffective for the treatment and prevention of vascular restenosis. See xe2x80x9cPrevention of Restenosis after Percutaneous Transluminal Coronary Angioplasty: The Search for a xe2x80x98Magic Bulletxe2x80x99xe2x80x9d, Hermans et al., American Heart Journal 122: 171-187 (July 1991).
In the pathogenesis of restenosis, excessive cell proliferation and migration occurs as a result of growth factors produced by cellular constituents in the blood and the damaged arterial vessel wall, which factors mediate the proliferation of smooth muscle cells in vascular restenosis.
Agents that inhibit the proliferation and/or migration of aortal smooth muscle cells are useful in the treatment and prevention of restenosis. The present invention provides for the use of compounds as aortal smooth muscle cell proliferation inhibitors and, thus, inhibitors of restenosis.
The present invention provides compounds with nitrogen-containing non-basic side chains of formula I 
wherein
R1 and R2, independently, are H, OH, O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94Ar, Oxe2x80x94C(O)xe2x80x94Oxe2x80x94Ar, Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), chloro, fluoro, or bromo;
V is S, O, or CH2CH2;
W is CHOH, C(O), or CH2;
X is (CH2)n, or (CH2)mC(O);
R3 and R4 each, independently, are H, C1-C6 alkyl, C(O)xe2x80x94(C1-C6 alkyl), C(O)xe2x80x94NHxe2x80x94(C1-C6 alkyl), C(O)xe2x80x94Ar, or together with the nitrogen to which they are attached form 1-pyrrolidinyl, 1-piperidinyl, or a 5- or 6-membered imide or cyclic amide;
m is 1 or 2;
n is 1, 2, or 3; and
Ar is optionally substituted phenyl;
provided that at least one of X, R3 , and R4 contain a carbonyl functional group.
The present invention also provides compounds with nitrogen-containing non-basic side chains of formula II 
wherein
R1 and R2, independently, are H, OH, O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94Ar, Oxe2x80x94C(O)xe2x80x94Oxe2x80x94Ar, Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), chloro, fluoro, or bromo;
V is S, O, or CH2CH2;
W is CHOH, C(O), or CH2;
Y is (CH2)n, CH(C1-C4 alkyl);
n is 1, 2, or 3; and
Ar is optionally substituted phenyl.
The present invention further provides compounds with nitrogen-containing non-basic side chains of formula III 
wherein
R1 and R2, independently, are H, OH, O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94Ar, Oxe2x80x94C(O)xe2x80x94Oxe2x80x94Ar, Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), chloro, fluoro, or bromo;
V is S, O, or CH2CH2;
W is CHOH, C(O), or CH2;
Z is a bond or CH2;
R5 is C(O)xe2x80x94(C1-C6 alkyl); and
Ar is optionally substituted phenyl.
Compounds of the current invention may have an asymmetric center. Thus, such compounds can have an R- or S-configuration, or a mixture thereof. All such isomers are considered part of this invention.
The present invention also provides pharmaceutical compositions containing compounds of formula I, formula II, and formula III, optionally containing estrogen or progestin, and the use of such compounds, alone, or in combination with estrogen or progestin, for alleviating the symptoms of post-menopausal symptoms, particularly osteoporosis, cardiovascular related pathological conditions, and estrogen-dependent cancer. As used herein, the term xe2x80x9cestrogenxe2x80x9d includes steroidal compounds having estrogenic activity such as, for example, 17xcex2-estradiol, estrone, conjugated estrogen (e.g., Premarin(copyright)), equine estrogen, 17xcex1-ethynyl estradiol, and the like. As used herein, the term xe2x80x9cprogestinxe2x80x9d includes compounds having progestational activity such as, for example, progesterone, norethynodrel, norgestrel, megestrol acetate, norethindrone, and the like.
The present invention further provides the use of the compounds of the present invention for inhibiting uterine fibroid disease and endometriosis in women and aortal smooth muscle cell proliferation, particularly restenosis, in humans.
General terms used in the description of compounds of the present invention bear their usual meanings. For example, xe2x80x9cC1-C4 alkylxe2x80x9d refers to aliphatic chains of 1 to 4 carbon atoms including methyl, ethyl, propyl, isopropyl, butyl, n-butyl, and the like; and xe2x80x9cC1-C6 alkylxe2x80x9d encompasses the groups included in the definition of xe2x80x9cC1-C4 alkylxe2x80x9d in addition to groups such as pentyl, isopentyl, hexyl, isohexyl, and the like. xe2x80x9cC4-C6 alkylxe2x80x9d refers to aliphatic chains of 4 to 6 carbon atoms including butyl, n-butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
The term xe2x80x9csubstituted phenylxe2x80x9d refers to a phenyl group having one or more substituents selected from the group consisting of C1-C4 alkyl, C1-C5 alkoxy, hydroxy, nitro, chloro, fluoro, or tri(chloro or fluoro)methyl. xe2x80x9cC1-C5 alkoxyxe2x80x9d represents a C1-C5 alkyl group attached through an oxygen bridge such as, for example, methoxy, ethoxy, n-propoxy, isopropoxy, and the like.
It should also be understood that as used herein, references to alkyl and alkoxy structures also include cycloalkyl and cycloalkoxy groups where the number of carbons within the structure is at least 3.
Further, xe2x80x9cimidexe2x80x9d is understood to indicate a heterocyclic structure wherein a nitrogen atom is adjacent to two carbonyl functional groups. An xe2x80x9camidexe2x80x9d is understood to be a structure having a nitrogen atom adjacent to a single carbonyl functional group, such amide may be cyclic.
Preferred compounds of this invention include compounds of formula I wherein any or all of the following limitations apply: V is S; W is C(O); and X is (CH2)2 or CH2C(O), especially (CH2)2. Especially preferred compounds of formula I are those wherein all of the preceding limitations apply.
Other preferred compounds of formula I include those compounds wherein R1 and R2 are OH, Oxe2x80x94C(O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94Ar, or Oxe2x80x94C(O)xe2x80x94Oxe2x80x94Ar, especially OH or OCH3. Of these, compounds wherein R1 and R2 are the same as one another are particularly preferred.
Certain R3 and R4 groups also demonstrate preferable characteristics. For example, those compounds of formula I wherein R3 and R4 together with the nitrogen to which they are attached form 1-pyrrolidinyl, 1-piperidinyl, or a 5- or 6-membered imide or cyclic amide are preferred. A further preferred subgroup of the preferred 1-pyrrolidinyl, 1-piperidinyl, imide, and cyclic amide compounds include those compounds wherein R1 and R2 are OH or OCH3.
Most especially preferred compounds of formula I include those having all of the aforementioned limitations, that is, compounds wherein V is S; W is C(O); X is (CH2)2 or CH2C(O), especially (CH2)2; R1 and R2 are OH, Oxe2x80x94C(O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94Ar, and Oxe2x80x94C(O)xe2x80x94Oxe2x80x94Ar, especially OH or OCH3, particularly wherein R1 and R2 are the same as one another; and R3 and R4, together with the nitrogen to which they are attached form 1-pyrrolidinyl, 1-piperidinyl, or a 5- or 6-membered imide or cyclic amide.
In keeping with the scope of this invention, the preferred compounds of formula I are limited to those wherein at least one carbonyl functional group is present at a position adjacent to the nitrogen in the 3- side chain. That is, at least one of X, R3, and R4 must contain a carbonyl functional group.
Other preferred compounds of this invention include compounds of formula II wherein any or all of the following limitations apply: V is S; W is C(O); and Y is CH2 or CH(CH3). Especially preferred compounds of formula II are those wherein all of the preceding limitations apply.
Other preferred compounds of formula II include those compounds wherein R1 and R2 are OH, Oxe2x80x94C(O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94Ar, or Oxe2x80x94C(O)xe2x80x94Oxe2x80x94Ar, especially OH or OCH3. Of these, compounds wherein R1 and R2 are the same as one another are particularly preferred.
Yet other preferred compounds of this invention include compounds of formula III wherein any or all of the following limitations apply: V is S; W is C(O); and Z is a bond or CH2. Especially preferred compounds of formula III are those wherein all of the preceding limitations apply.
Other preferred compounds of formula II include those compounds wherein R1 and R2 are OH, Oxe2x80x94C(O)xe2x80x94(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94O(C1-C6 alkyl), Oxe2x80x94C(O)xe2x80x94Ar, or Oxe2x80x94C(O)xe2x80x94Oxe2x80x94Ar, especially OH or OCH3. Of these, compounds wherein R1 and R2 are the same as one another are particularly preferred.
Preferred methods of this invention obviously include those wherein preferred compounds are used.
The compounds of the present invention are derivatives of benzo[b]thiophene which is named and numbered according to the Ring Index, The American Chemical Society, as follows. 
In the processes for preparing the compounds of the present invention, the starting material is generally a precursor of formula below, which can be prepared via known 
Typically, the two hydroxy groups are protected by known hydroxy protecting groups that are capable of resisting acylation under standard Friedel-Crafts conditions and subsequent reduction by a strong reducing agent. Preferred hydroxy protecting groups are C1-C4 alkyl, and methyl is especially preferred. See, e.g., U.S. Pat. Nos. 4,133,814; 4,380,635; and 4,418,068, each of which is herein incorporated by reference, J. W. Barton, xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, J. G. W. McOmie (ed.), Plenum Press, New York, N.Y., 1973, Chapter 2, and T. W. Green, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, John Wiley and Sons, New York, N.Y., 1981, Chapter 7.
Following preparation of the desired protected precursor, the precursor is acylated, using standard Friedel-Crafts conditions, according to acylation methods disclosed in the above-incorporated United States patents.
All reagents obtained from commercial sources were used without further purification unless otherwise indicated. 1H-NMR and 13C-NMR were measured as indicated at 300 and 75 MHz respectively. 1H-NMR chemical shifts are reported as xcex4 values in ppm relative to the NMR solvent employed. 1H-NMR coupling constants are reported in Hertz (Hz) and refer to apparent multiplicities. Multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), comp (complex), br (broad), and app (apparent). Column chromatography was performed according to the method of Still et. al. (Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43:2923) unless otherwise indicated with EM Science silica gel (230-400 mesh ASTM). Radial chromatography was performed on a Chromatotron (Harrison Research) using 1, 2, or 4 mm thick plates. All air and/or moisture sensitive reactions were run under an argon or nitrogen atmosphere in rigorously dried glassware. In all cases, concentrations were performed under reduced pressure with a rotary evaporator.
Four general synthetic routes, which were used to prepare compounds of the present invention, are outlined below, wherein R1 and R2 are as defined above. 
Compounds of the present invention in which W is CHOH are prepared following sodium ethanethioate deprotection by dissolution in an appropriate solvent and reaction with reducing agent, such as, for example, lithium aluminum hydride, under an inert gas such as nitrogen.
The amount of reducing agent used in this reaction is an amount sufficient to reduce the carbonyl group to an alcoholic group (CHOH). Generally, an excess of the reducing agent per equivalent of the substrate is used.
Suitable solvents include any solvent or mixture of solvents that will remain inert under reducing conditions, such as, for example, diethyl ether, dioxane, and tetrahydrofuran (THF). The anydrous form of these solvents is preferred, and anhydrous THF is especially preferred.
The temperature employed in this step is that which is sufficient to effect completion of the reduction reaction. Ambient temperature, in the range from about 17xc2x0 C. to about 25xc2x0 C., generally is adequate.
The length of time for this step is that amount necessary for the reaction to occur. Typically, this reaction takes from about 1 to about 20 hours. The optimal time can be determined by monitoring the progress of the reaction via conventional chromatographic techniques.
A compound of the present invention wherein W is CHOH may be further reduced to provide compounds wherein W is methylene via standard procedures. This is accomplished by suspending the compound in an appropriate solvent and cooling under an inert gas such as nitrogen. To this suspension is added a suitable trialkyl silane reducing agent, preferrably triethyl silyl, and a reasonably strong protic acid such as hydrochloric acid, trifluoroacetic acid, and the like.
Suitable solvents can be any solvent or mixture of solvents that remain inert under the reaction conditions employed in the process. For example, halogenated alkane solvents such as dichloromethane and 1,2-dichloroethane, as well as haloaromatics such as chlorobenzene and the like may be used. of these, dichloromethane is preferred.
The temperature employed in this step is that which is sufficient to effect completion of the present reduction process. Typically, the reaction is cooled to about 0xc2x0 C. and the reaction solution is kept on ice until the reaction is complete; however, ambient temperature also is satisfactory. In general, this reaction is completed in less than three hours, and the progress of the reaction can be monitored via standard techniques. The product of this reaction is extracted and purified via standard techniques.
Alternatively, ketones of the type shown in general route #1 prior to alkylation can be reduced to the compound wherein W is methylene. In this process, the R1 and R2 hydroxy protecting groups, which are preferrably methyl, optionally are removed, and the protected or deprotected compound is reacted with a reducing agent such as lithium aluminum hydride in the presence of an inert solvent having a boiling point in the range from about 150xc2x0 C. to about 200xc2x0 C. While each step of this process is preferrably carried out in separate vessels, it is possible to carry out each step of the present process in the same vessel.
The amount of reducing agent used in this reaction is an amount sufficient to reduce the carbonyl group to a methylene group. Generally, an excess of the reducing agent per equivalent of the substrate is used.
The solvent used in the present process is required to have a relatively high boiling point, in the range from about 150xc2x0 C. to about 200xc2x0 C., as represented by solvents such as, for example, n-propylbenzene, diglyme (1,1xe2x80x2-oxybis[2-methoxyethane]), and anisole, and Red-Al(copyright) (sodium bis(2-methoxyethoxyaluminum hydride)), which also is used as the reducing agent. When the R1 and R2 substituents of compounds of the present invention are hydroxy protecting groups, n-propylbenzene is the preferred solvent. When such protecting groups are first optionally removed prior to reduction, Red-Al is the preferred reagent.
The temperature used in this reaction is that which is sufficient to complete the reduction reaction. Preferrably, the reaction mixture is heated to reflux for about 15 minutes to about 6 hours, and allowed to cool to ambient temperature. When R1 and R2 are hydroxy protecting groups, a small amount of deionized water is added to the mixture followed by the addition of a small aliquot of 15% sodium hydroxide. When R1 and R2 are OH, the reaction is carefully quenched with excess 1.0 N hydrochloric acid. The optimal amount of time for these reactions to run, typically from about 10 minutes to about 3 hours, can be determined by monitoring the progress of the reaction via standard techniques.
Following reduction of W to CHOH or CH2, the appropriate groups can be appended on as described previously.
When a Oxe2x80x94C(O)xe2x80x94(C1-C6 alkyl) or Oxe2x80x94C(O)xe2x80x94Ar group is desired at R1 and R2, a dihydroxy compound of formula I, II, or III is reacted with an agent such as acyl chloride, bromide, cyanide, or azide, or with an appropriate anhydride or mixed anhydride. The reactions are conveniently carried out in a basic solvent such as pyridine, lutidine, quinoline or isoquinoline, or in a tertiary amine solvent such as triethylamine, tributylamine, methylpiperidine, and the like. The reaction also may be carried out in an inert solvent such as ethyl acetate, dimethylformamide, dimethylsulfoxide, dioxane, dimethoxyethane, acetonitrile, acetone, methyl ethyl ketone, and the like, to which at least one equivalent of an acid scavenger, such as a tertiary amine, has been added. If desired, acylation catalysts such as 4-dimethylaminopyridine or 4-pyrollidinopyridine may be used. See, e.g., Haslam, et al., Tetrahedron, 36:2409-2433 (1980).
The acylation reactions which provide the aforementioned R1 and R2 groups are carried out at moderate temperatures in the range from about xe2x88x9225xc2x0 C. to about 100xc2x0 C., frequently under an inert atmosphere such as nitrogen gas. However, ambient temperature is usually adequate for the reaction to run.
Such acylations of the hydroxy group also may be performed by acid-catalyzed reactions of the appropriate carboxylic acids in inert organic solvents or heat. Acid catalysts such as sulfuric acid, polyphosphoric acid, methanesulfonic acid, and the like are used.
The aforementioned R1 and R2 groups also may be provided by forming an active ester of the appropriate acid, such as the esters formed by such known reagents as dicyclohexylcarbodiimide, acylimidazoles, nitrophenols, pentachlorophenol, N-hydroxysuccinimide, and 1-hydroxybenzotriazole. See, e.g., Bull. Chem. Soc. Japan, 38:1979 (1965), and Chem. Ber., 788 and 2024 (1970).
Each of the above techniques that provide Oxe2x80x94C(O)xe2x80x94(C1-C6 alkyl) and Oxe2x80x94C(O)xe2x80x94Ar groups are carried out in solvents as discussed above. These techniques, which do not produce an acid product in the course of the reaction, of course, do not necessitate the use of an acid scavenger in the reaction mixture.
When a compound is desired in which R1 and R2 is Oxe2x80x94SO2xe2x80x94(C4-C6 alkyl), a dihydroxy compound is reacted with, for example, a derivative of the appropriate sulfonic acid such as a sulfonyl chloride, bromide, or sulfonyl ammonium salt, as taught by King and Monoir, J. Am. Chem. Soc., 97:2566-2567 (1975). The dihydroxy compound also can be reacted with the appropriate sulfonic anhydride. Such reactions are carried out under conditions such as were explained above in the discussion of reaction with acid halides and the like.
Compounds of formula I, II, and III can be prepared so that R1 and R2 are different biological protecting groups or, preferably, the same biological protecting group. Preferred protecting groups include OCH3, Oxe2x80x94C(O)xe2x80x94C(CH3)3, Oxe2x80x94C(O)xe2x80x94C6Hs, and Oxe2x80x94SO2xe2x80x94(CH2)3xe2x80x94CH3.
The term xe2x80x9cbiological protecting groupsxe2x80x9d refers to those R1 and R2 substituents which delay, resist, or prohibit removal of such groups in a biological system such as, for example, following administration of a compound of the present invention containing the above-described R1 and R2 groups to a human. Such compounds also are useful for the methods herein described, especially when W is CH2.